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Disease Modeling of Skeletaland Cardiac Muscle in DMD/BMD using Patient-Specific iPS Cells

使用患者特异性 iPS 细胞对 DMD/BMD 中的骨骼肌和心肌进行疾病建模

基本信息

批准号：
10390553
负责人：
Rita C. R. Perlingeiro
金额：
$ 20.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390553
关键词：
3-Dimensional Action Potentials Affect Amyotrophic Lateral Sclerosis Axon Becker Muscular Dystrophy Biological Biological Assay Biological Process Biology Calcium Cardiac Cardiac Myocytes Cell Line Cells Chemicals Communities Creatine Kinase Defect Detection Development Disease Disease model Drug Screening Duchenne muscular dystrophy Dystrophin Electrophysiology (science)Functional disorder Generations Goals Heart Atrium In Vitro Investigation Laboratories Link Literature Long QT Syndrome Measurement Membrane Methods Microelectrodes Modeling Molecular Molecular Profiling Mus Muscle Fibers Muscle function Muscle satellite cell Mutation Myocardium Myopathy Nodal Paper Pathogenesis Patients Phenotype Pluripotent Stem Cells Population Proteins Publishing Regenerative Medicine Research Resources Role Sampling Signal Pathway Skeletal Muscle Somatic Cell Spinal Muscular Atrophy System Technology Therapeutic Tissues Validation Ventricular Work cell type cohort disease phenotype drug discovery dystrophinopathy gene correction human pluripotent stem cell in vivo induced pluripotent stem cell induced pluripotent stem cell technology insight instrument mutant osteoprogenitor cell patch clamp programs screening skeletal small molecule stem cells transcriptome

项目摘要

Summary This project aims to establish a reliable platform to use patient-specific induced pluripotent stem (iPS) cells to model Duchenne Muscular Dystrophy (DMD) and Becker MD (BMD) in the Petri dish, allowing not only for better insight on the pathogenesis of dystrophin-associated disorders, but specially for the development of a relevant system for drug screening. Reprogramming technology provides an unprecedented opportunity to generate large numbers of patient-specific cell types for in vitro disease modeling and drug discovery. Accordingly, iPS cells have been used extensively for these purposes for several disorders, including amyotrophic lateral sclerosis, long-QT syndrome, and spinal muscular atrophy, among others. However to date, there has been scarce literature on the use of this approach to model skeletal muscle disorders, and none studying both skeletal and cardiac muscle in the context of DMD and BMD. Our research group has pioneered methods to derive large quantities of skeletal myogenic progenitor cells from mouse and human pluripotent stem cells, and validated these in vitro and in vivo. Specifically relevant for this proposal, we have recently published a paper focusing on the in vitro maturation of iPS cells towards the skeletal muscle lineage (eLIFE, 2019), which is critical for proper disease modeling. For this project, we have samples from ten DMD/BMD patients, encoding various distinct mutations and displaying mild to severe phenotypes. iPS cells from these samples will be used to produce large numbers of DMD/BMD skeletal myotubes and cardiomyocytes. The hypothesis behind this project is that we will be able to recapitulate disease phenotypes in vitro, including membrane fragility, calcium handling, contraction using three-dimensional myobundles, and electrophysiology measurements. We foresee that molecular/biological signatures resulting from this work will not only enhance our understanding of the pathophysiology behind DMD/BMD, but may also serve as in vitro screening for potential treatments. To validate this hypothesis, we will have control cohort samples, in which we genetically introduce selected DMD mutations in unaffected iPS cells and/or correct selected DMD mutations. The work we propose here, of not only generating skeletal and cardiac muscle from iPS cells but also studying the underlying biology, holds tremendous potential for exploring phenotypes of different mutations, in vitro disease modeling in general, and drug discovery.

总结